How effective is doxazosin compared with chlorthalidone in the treatment of hypertension?

Journal of Family Practice, July, 2000 by Peter G. Koval, Todd McDiarmid

The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000; 283:1967-75.

* BACKGROUND Hypertension is associated with an increased risk of morbidity and mortality. This study was undertaken to evaluate if newer classes of antihypertensive medications reduce the risk of cardiovascular events compared with an active control (diuretics) that has demonstrated a reduction in long-term clinical trials.

* POPULATION STUDIED The Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT) includes a total of 42,448 participants recruited from 625 centers in the United States, Canada, Puerto Rico, and the US Virgin Islands. Participants in the trial were men and women 55 years or older with hypertension (systolic blood pressure [SBP] [is greater than or equal to] 140 mm Hg or diastolic blood pressure [DBP] [is greater than or equal to] 90 mm Hg, or took medication for hypertension) and at least 1 additional risk factor for coronary heart disease (CHD). Follow-up was scheduled for 6 years. The doxazosin and chlorthalidone groups included 24,335 patients (mean age=67 years; 53% men; 47% non-Hispanic white) who were followed for a median of 3.3 years.

* STUDY DESIGN AND VALIDITY Eligible patients were initially randomized (allocation assignment concealed) to one of the 4 drugs (chlorthalidone, amlodipine, lisinopril, or doxazosin) as a firstline agent and then other drugs (atenolol, reserpine, clonidine, or hydralazine) were added in an open-label fashion, if necessary. The treatment goals were a DBP [is less than] 90 mm Hg and an SBP [is less than] 140 mm Hg. Following the initial titration visits, participants were seen every 3 months during the first year, and every 4 months thereafter. The randomization process provided an equal percentage of patients previously treated for hypertension, atherosclerotic cardiovascular disease, type 2 diabetes, smoking, low high-density lipoprotein, low ventricular hypertrophy (LVH) by electrocardiogram, and LVH by echocardiogram. The chlorthalidone group and the doxazosin group lost similar percentages of patients to follow-up, 3.2% and 3.7%, respectively, at the time of this analysis. The percentage of patients at years 3 and 4 who were still taking chlorthalidone (or another diuretic) was 87% and 86%, respectively. Of the patients taking doxazosin, only 76% were taking the drug at year 3 and 75% at year 4. By year 4, 40% of the chlorthalidone group was receiving step-up therapy, while 47% of the patients taking doxazosin required additional medications. All of these efforts to provide fair comparisons and use of the intention-to-treat analysis make this a valid comparative study.

* OUTCOMES MEASURED Primary outcome measures were fatal CHD and nonfatal myocardial infarction (MI). Secondary outcome measures included all-cause mortality, stroke, and combined cardiovascular disease (CHD death, nonfatal MI, stroke, angina, coronary revascularization, congestive heart failure [CHF], and peripheral arterial disease).

* RESULTS There was no difference between the doxazosin and chlorthalidone groups in the primary outcomes of fatal CHD or nonfatal MI or the secondary outcome of all-cause mortality. The doxazosin group did, however, have a higher risk of stroke than those patients treated with chlorthalidone (4.2% vs 3.6%; relative risk [RR]= 1.19; 95% confidence interval [CI], 1.01-1.40; P=.04; number needed to harm [NNH]=167) and an increased risk of combined cardiovascular disease (25.5% vs 21.8%; RR = 1.25; 95% CI, 1.17-1.33; P [is less than] .001; NNH=27). Cardiovascular disease subset analysis demonstrated statistically significant differences in angina, coronary revascularization, and CHF. The difference between the groups was most remarkable for CHF, because a doubling of events occurred with doxazosin compared with chlorthalidone (8.1% vs 4.4%; RR=2.04; 95% CI, 1.79-2.32; P [is less than] .001; NNH=27).

RECOMMENDATIONS FOR CLINICAL PRACTICE

This study demonstrates a reduction of risk for combined cardiovascular disease events, particularly CHF, in a hypertensive population treated with chlorthalidone compared with doxazosin. There continues to be no compelling indication for the use of doxazosin as a first-line antihypertensive medication. This trial reinforces the Joint National Committee VI recommendations for initial selection of antihypertensive medications by proving that chlorthalidone is superior to doxazosin. The absence of a placebo arm in ALLHAT does not allow conclusions about an independent causal impact of doxazosin on event rates. The same or larger increases in poor outcomes may also be seen without doxazosin. The potential benefit of doxazosin in relieving symptoms of benign prostatic hypertrophy is a situation for considering use that was not addressed in this trial.